Abstract: Infection with Helicobacter pylori (H. pylori) and autoimmune gastritis both cause chronic inflammation and increase the risk of gastric cancer. Metaplasia in various tissues (lungs, pancreas, stomach) is associated with chronic inflammation and indicative of disease and an increased risk for developing cancer. In the stomach, metaplastic changes are induced in gastric epithelial cells, and >95% of all gastric cancers are epithelial cell derived adenocarcinomas. There is a critical gap in our understanding how individual immune cells and the inflammatory mediators they secrete (e.g. cytokines) regulate gastric metaplasia and gastric carcinogenesis. This application investigates the importance of a cytokine (IL-13) and immune cell type (mast cells) in inducing gastric metaplasia and promoting the development of gastric tumors. Experiments include a variety of genetically modified mouse models of gastritis, single cell transcriptomics of mouse and human cells, tumorigenesis studies, and analyses of human biopsies to develop mechanistic insight into how mast cells and IL-13 signaling regulate gastric metaplasia and tumorigenesis. Understanding how inflammation induces metaplasia and tumor development could improve the ability to identify individuals at an increased risk of disease progression, and new immune based strategies to prevent and treat preneoplastic lesions associated with gastric diseases, including gastric cancer. Work performed during this R56 funding period generate additional preliminary data to address some of the critiques from recent reviews of our application. SPECIFIC AIMS: Metaplasia is associated with inflammation and indicative of disease and an increased risk for developing cancer. In the stomach, Helicobacter pylori (H. pylori) infection and autoimmune gastritis both cause chronic inflammation, metaplasia, and increase the risk of gastric cancer. Metaplastic changes are induced in gastric epithelial cells, and >95% of all gastric cancers are epithelial cell-derived adenocarcinomas. How specific components of inflammatory responses induce and regulate gastric metaplasia and gastric carcinogenesis is poorly understood. Determining the immune cells and cytokines that induce metaplasia and support its progression to cancer (adenocarcinoma) are essential in defining the pathophysiology of this disease process and could reveal new immune-based strategies to prevent and treat disease. We recently discovered that mice lacking the IL-4RA receptors (Il4ra-/-) failed to develop metaplasia in a model of chronic gastritis and metaplasia. The IL-4RA is a component of receptors for two cytokines, IL-4 and IL-13. While IL-4 levels were nearly absent, IL-13 was secreted at relatively high levels in the gastric mucosa in two different mouse models of gastritis and gastric epithelium express IL-13 receptors. Surprisingly, most of the IL- 13 secreting cells were mast cells. Recent data in mouse models have associated IL-13 production ...